Literature Review

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n engl j med 380;2 nejm.org January 10, 2019 121

established in 1812 January 10, 2019 vol. 380 no. 2

From Centre Hospitalier Monkole, Kin- shasa, Democratic Republic of Congo (L.T.); the Department of Medicine, Uni- versity Health Network and Mt. Sinai Hospital, and the University of Toronto, Toronto (G.T.); the Kenya Medical Re- search Institute (KEMRI)–Wellcome Trust Research Program, Kilifi, Kenya (T.N.W.); the Department of Medicine, Imperial College London, London (T.N.W.); Hos- pital Pediátrico David Bernardino, Luanda, Angola (B.S.); Mbale Clinical Research Institute and Mbale Regional Referral and Teaching Hospital–Busitema Univer- sity, Mbale, Uganda (P.O.-O.); the Divi- sion of Hematology, Department of Pedi- atrics, Cincinnati Children’s Hospital (A.L., S.E.S., T.S.L., P.T.M., R.E.W.), University of Cincinnati College of Medicine (A.L., P.T.M., R.E.W.), and the Global Health Center, Cincinnati Children’s Hospital Medical Center (S.E.S., P.T.M., R.E.W.), Cincinnati; and Cohen Children’s Medical Center, New Hyde Park, and the Zucker School of Medicine at Hofstra/Northwell, Hempstead — both in New York (B.A.). Address reprint requests to Dr. Ware at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, or at russell . ware@ cchmc . org.

*A complete list of the REACH Investiga- tors is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on December 1, 2018, at NEJM.org.

BACKGROUND Hydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hy- droxyurea in low-resource settings. METHODS We enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibil- ity (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival). RESULTS A total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient- years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence in- terval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88). CONCLUSIONS Hydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, in- fections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731.)

a b s t r a c t

Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa

Léon Tshilolo, M.D., Ph.D., George Tomlinson, Ph.D., Thomas N. Williams, M.D., Ph.D., Brígida Santos, M.D., Peter Olupot-Olupot, M.D., Ph.D., Adam Lane, Ph.D., Banu Aygun, M.D., Susan E. Stuber, M.A., Teresa S. Latham, M.A.,

Patrick T. McGann, M.D., and Russell E. Ware, M.D., Ph.D., for the REACH Investigators*

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Sickle hemoglobinopathies are com-mon and life-threatening genetic disorders. Homozygous hemoglobin S (HbSS) is the most severe genotype, and together with hemo- globin Sβ0 thalassemia, is called sickle cell ane- mia.1 On deoxygenation, erythrocytes become sickle-shaped, rigid, adhesive, and prone to lysis; blood flow is blocked within small vessels, lead- ing to ischemic tissue injury.1 In the United States, approximately 100,000 persons are affected,2 most of whom have numerous acute and chronic medi- cal complications that lead to poor quality of life and early death.1,3 On a global scale, the incidence of sickle hemoglobinopathies is greatest in sub- Saharan Africa, with more than 300,000 babies with sickle cell disease born annually, represent- ing approximately 1% of births in the region.4

In high-resource settings such as the United States and Europe, as well as Jamaica and other Caribbean settings, the early identification of chil- dren with sickle cell anemia by means of neonatal screening allows for comprehensive care that in- cludes simple, effective, and lifesaving interven- tions with penicillin prophylaxis, pneumococcal immunizations, and caregiver education.5-7 The advent of routine transcranial Doppler screening to identify children at risk for stroke, along with access to safe erythrocyte transfusions, has further contributed to marked decreases in morbidity.8 To date, however, very few settings in sub-Saharan Africa have established screening programs for sickle cell anemia, and specialized treatment is available at only a few large, urban centers.

Hydroxyurea was first shown to induce fetal hemoglobin production more than 30 years ago9 and is now a Food and Drug Administration– approved treatment for sickle cell anemia in both children (Siklos, Addmedica) and adults (Hydrea and Droxia, Bristol-Myers Squibb). By means of the induction of fetal hemoglobin and other beneficial changes, including mild myelosuppression, hy- droxy urea therapy has been shown to have clinical efficacy in reducing the incidence of acute vaso- occlusive events,10,11 ameliorating chronic organ damage,12 and prolonging survival.13,14 Evidence- based guidelines from the National Heart, Lung, and Blood Institute recommend offering hydroxy- urea treatment to persons with sickle cell anemia as early as 9 months of age.15

Whether hydroxyurea will be safe and effec- tive in Africa is unclear. Coexisting conditions such as malaria, other infectious diseases that are endemic to the area, and malnutrition may

increase the incidence of toxic effects and limit treatment responses. We conducted an interna- tional trial, Realizing Effectiveness across Conti- nents with Hydroxyurea (REACH), to investigate the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia liv- ing in sub-Saharan Africa.

M e t h o d s

Trial Design

We designed this phase 1–2, open-label, interna- tional trial to assess the feasibility, safety, and benefits of hydroxyurea treatment in young chil- dren with sickle cell anemia living in sub-Saharan Africa. The two-stage trial design has been de- scribed previously16 and included a built-in pause in enrollment to ensure the safety of the initial dose level (Fig. S1 in the Supplementary Appen- dix, available with the full text of this article at NEJM.org). Children 1 to 10 years of age were recruited at four clinical trial sites in sub-Saharan Africa (Hospital Pediátrico David Bernardino in Luanda, Angola; Centre Hospitalier Monkole in Kinshasa, Democratic Republic of Congo; Kilifi District Hospital in Kilifi, Kenya; and Mbale Re- gional Referral Hospital in Mbale, Uganda), with a goal of treating 150 participants per site with once-daily oral hydroxyurea. At each site, enroll- ment was paused to allow for the evaluation of the 3-month incidence of hematologic toxic ef- fects among the first 53 participants enrolled.16

The protocol (available at NEJM.org) was de- signed by the authors and approved by all appro- priate institutional review boards or ethics com- mittees, as well as by national regulatory groups. A parent or legal guardian provided written in- formed consent for each participant to enroll and begin the screening process. A full list of the in- vestigative teams, including the physicians, nurs- es, pharmacists, and laboratory and data person- nel who received specific protocol training, is provided in the Supplementary Appendix. Local trial teams collected the data, which were mon- itored and analyzed by the data management center. The first draft of the manuscript was written by the first and last authors, with contri- butions by all the authors. All the authors made the decision to submit the manuscript for publi- cation. The sponsors had no oversight or involve- ment in data collection and analysis or in the writing and submission of the manuscript. The last author vouches for the accuracy and com-

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pleteness of the data and for the fidelity of the trial to the protocol.

Drug Treatment and Dose Escalation

Hydroxyurea capsules were donated by Bristol- Myers Squibb, which had no role in the trial de- sign or conduct, the data collection or analysis, or the manuscript preparation or review. After a 2-month screening period that was used to collect pretreatment clinical and laboratory data, the starting dose of hydroxyurea was 15 to 20 mg per kilogram of body weight per day. After 6 months of treatment, the hydroxyurea dose was esca- lated by 2.5 to 5.0 mg per kilogram per day every 2 months on the basis of peripheral-blood counts to determine a maximum tolerated dose, which was defined as a stable daily dose that caused mild bone marrow suppression without toxic effects — typically, an absolute neutrophil count of less than 4000 per cubic millimeter. To ensure the safety of the participants, the dose level was monitored at each visit by trial staff, who entered the results of the complete blood count and re- ticulocyte count into an interactive online calcu- lator tool before the drug was dispensed.

End Points

The primary safety end point was hematologic dose-limiting toxic effects in the first 3 months of hydroxyurea treatment in the first 133 children enrolled at each clinical trial site; the expected and allowable rates of this end point were 20% and 30%, respectively, on the basis of published toxicity data, with type I and II error rates of 10%.16 Protocol-specified thresholds for toxic effects in- volving laboratory variables included a hemoglo- bin level of less than 4.0 g per deciliter, an abso- lute neutrophil count of less than 1000 per cubic millimeter, an absolute reticulocyte count of less than 80,000 per cubic millimeter unless the hemo- globin level was more than 7.0 g per deciliter, and a platelet count of less than 80,000 per cubic mil- limeter. Additional trial end points included as- sessments of feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival).

Data Collection and Storage

All the trial data were collected and entered into a REDCap Internet-based data-capture system. Separate REDCap environments were developed in English, Portuguese, and French, which were

the official languages at each clinical site.16 Data on clinical adverse events of grade 2 or higher were collected during both the screening (pretreatment) phase and the treatment phase. Trial monitoring used a remote system and on-site evaluations. Data on adverse events were collected and curated, with review of source documentation whenever avail- able. Deaths were further evaluated with the use of the World Health Organization (WHO) verbal autopsy form that has previously been validated for children with sickle cell anemia.17

Statistical Analysis

The Simon two-stage design for the primary safety end point (hematologic dose-limiting toxic effects in the first 3 months of hydroxyurea treatment) has been described previously.16 Secondary end points regarding feasibility, safety, and benefits were summarized with means and standard de- viations or percentages, as appropriate. We used a competing-risk approach to estimate the cumu- lative incidence of death or withdrawal. Labora- tory values at baseline and at 12 months were compared by Student’s t-test. Rates of clinical ad- verse events during the pretreatment phase and during the treatment phase were presented as the number of events per 100 patient-years and com- pared by the incidence rate ratio with 95% con- fidence intervals, all of which were calculated from Poisson regression with the use of general- ized estimating equations to account for cluster- ing and overdispersion. A similar approach was used to show the effect of increasing treatment duration, with events and time at risk during treat- ment divided into consecutive 6-month intervals. There were no adjustments for multiple compari- sons. All the statistical analyses were performed with the use of R software, version 3.4.4.

R e s u l t s

Enrollment and Retention

All four trial sites proceeded to the second stage of the trial and met their enrollment goals. A total of 635 children had consent provided by a parent or guardian and entered screening, 606 children completed screening and began receiving hydroxy- urea treatment, and 600 children (99.0%) com- pleted 3 months of the trial treatment (Fig. 1). The overall retention rate in the trial was 94.2% at 3 years of treatment (Fig. 2). A total of 33 children (5.4%) withdrew from the trial after treatment initiation. More than 98% of the trial visits were

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completed, including 91% within the scheduled visit window.

Hydroxyurea Dose

The initial mean (±SD) dose of hydroxyurea that was administered was 17.5±1.8 mg per kilogram per day, which was within the protocol-directed starting dose range of 15 to 20 mg per kilogram per day. The initial dose was fixed for 6 months in all the participants to allow for the assessment of laboratory and clinical adverse events. Dose esca- lation began at month 6, and to date, 515 children (85.0%) have reached a mean maximum tolerated dose of 22.5±4.9 mg per kilogram per day, with the dose ranging from 18.9±4.2 mg per kilogram per day in Angola to 25.3±4.8 mg per kilogram per day in Uganda. The mean time to reaching the maximum tolerated dose was 11±4 months, and the mean overall treatment duration was 29±9 months. The rate of adherence to medication was assessed at each scheduled visit, and more than 90% of assessments documented no missed dos- es. A brief drug shortage between February and April 2016 affected the administration of the medication at three sites but had no influence on the primary end point (Table S1 in the Supplemen- tary Appendix).

Adverse Events

Laboratory monitoring at scheduled visits and at unscheduled visits for illness identified dose-limit- ing toxic effects during the screening phase (a total of 2012 complete blood counts were performed over a period of 111 patient-years) and during the treatment phase (a total of 13,589 complete blood counts were performed over a period of 1469 pa- tient-years). Hematologic dose-limiting toxic ef- fects during the first 3 months (the primary safety end point) occurred in 5.1% of the participants overall, with the rate at each site being well below the protocol-specified thresholds for toxic events regarding laboratory variables. The rates of these safety events differed across sites, ranging from 0.8% to 8.3% (P = 0.01 by Fisher’s exact test) (Ta-

606 Initiated hydroxyurea treatment

635 Patients had consent provided by a parent or guardian and underwent screening

29 Were withdrawn during screening 11 Were ineligible 3 Had consent withdrawn 3 Relocated 6 Did not adhere to study regimen 2 Were lost to follow-up 4 Died

600 Completed 3 mo of study treatment

6 Were withdrawn during mo 0–3 1 Was ineligible 2 Did not adhere to study regimen 1 Was lost to follow-up 2 Died

588 Completed 12 mo of study treatment

12 Were withdrawn during mo 3–12 1 Was ineligible 1 Relocated 1 Did not adhere to study regimen 3 Were lost to follow-up 6 Died

415 Completed 24 mo of study treatment 162 Had not completed 24 mo of study

treatment before database lock

11 Were withdrawn during mo 12–24 4 Relocated 1 Did not adhere to study regimen 1 Was lost to follow-up 5 Died

235 Completed 36 mo of study treatment 177 Had not completed 36 mo of study

treatment before database lock

3 Were withdrawn during mo 24–36 1 Did not adhere to study regimen 2 Died

5 Completed 48 mo of study treatment 229 Had not completed 48 mo of study

treatment before database lock

1 Died after 36 mo

Figure 1. Screening, Enrollment, and Follow-up of the Participants.

The numbers of patients who withdrew from the trial or died are from the group of patients who completed treatment up to the respective time point.

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ble S2 in the Supplementary Appendix), and the random-effects pooled estimate was 4.5% (95% confidence interval [CI], 2.3 to 8.8). No signifi- cant differences between the screening and treat- ment phases were found with regard to the indi- vidual laboratory toxic-effect variables (Table 1), but slight differences were noted between sites (data not shown).

Laboratory Benefits

Laboratory variables at baseline revealed anemia with expected leukocytosis and reticulocytosis (Table 2). After 1 year of hydroxyurea treatment, the participants had significant increases in the hemoglobin level (increase of 1.0 g per deciliter; 95% CI, 0.8 to 1.0), the mean corpuscular volume (increase of 13 fl; 95% CI, 12 to 13), and the fetal hemoglobin level (increase of 12.5%; 95% CI, 11.8 to 13.1). During hydroxyurea treatment, the white- cell count, absolute neutrophil count, and absolute reticulocyte count significantly decreased, reflect- ing the intended mild bone marrow suppression, and these effects were sustained over time (Ta- ble 2). Similar results were recorded at each indi- vidual clinical trial site (data not shown).

Clinical Benefits

Comparison of event rates between the screening and treatment phases revealed significant reduc- tions in the incidence of all clinical adverse events (308.4 vs. 170.7 events per 100 patient-years; inci- dence rate ratio, 0.54; 95% CI, 0.48 to 0.62) and serious adverse events (10.8 vs. 4.4 events per 100 patient-years; incidence rate ratio, 0.47; 95% CI, 0.25 to 0.90) during hydroxyurea treatment. The investigators did not consider any of the adverse events or serious adverse events to be related to hydroxyurea treatment.

The overall rate of sickle cell–related events was significantly reduced (114.5 vs. 53.0 events per 100 patient-years; incidence rate ratio, 0.47; 95% CI, 0.38 to 0.57), and the rates of vaso-occlusive pain and the acute chest syndrome were both reduced (Table 1). The rates of infection also declined, in- cluding rates of nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72) and severe infection of grade 3 or higher (28.9 vs. 8.0 events per 100 patient-years; incidence rate ratio, 0.28; 95% CI, 0.19 to 0.42).

Effects on Survival

Analyses of additional key clinical events revealed significant reductions during hydroxyurea treat- ment in the rate of malaria infections (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), blood transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 events per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88). When grouped into 6-month time intervals, the rates of multiple life-threatening clinical events declined rapidly after the initiation of hydroxyurea therapy and dose escalation, with a sustained or improved benefit. Reductions in event rates over time were noted for all sickle cell–related clinical events, malaria, vaso-occlusive pain, transfusion, the acute chest syndrome, and death from any cause (Fig. 3).

D i s c u s s i o n

In this trial involving children with sickle cell ane- mia living in sub-Saharan Africa, we found that hydroxyurea treatment was feasible, reasonably safe, and had both laboratory and clinical benefits. Specifically, as compared with pretreatment rates, the rates of clinical events, including vaso-occlusive pain, infection, malaria, transfusion, and death, declined after 1 year of hydroxyurea treatment.

Enrollment was robust at all the clinical trial sites, with enthusiasm and support from local clinical research teams and populations of pa- tients, which showed the feasibility of conducting a large-scale clinical trial in sub-Saharan Africa. Hematologic dose-limiting toxic effects during the first 3 months of treatment (the primary safety end point) occurred in only a small number of par- ticipants, and the hydroxyurea dose was then safely escalated toward a maximum tolerated dose, similar to treatment protocols in the United States.15 Expected hematologic benefits occurred, with significant increases in the hemoglobin and fetal hemoglobin levels. Significant reductions were observed in the incidence rates of sickle cell– related clinical events, including vaso-occlusive pain, and major clinical events including infec- tion, malaria, transfusion, and death. No serious adverse events or deaths were considered by the investigators to be related to hydroxyurea treat-

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ment (Tables S3 and S4 in the Supplementary Appendix).

In the United States and Europe, hydroxyurea has emerged as a potent, disease-modifying thera- py with regulatory approvals for use in both chil- dren and adults. Although the primary mode of action of hydroxyurea is through the induction of fetal hemoglobin, this drug has multiple salu- tary effects on erythrocytes, leukocytes, and even endothelium that make it a beneficial oral treat- ment for this life-threatening disease, especially at the maximum tolerated dose.18 The WHO in- cludes hydroxyurea on its Model Lists of Essential Medicines for children and adults for the treatment of sickle hemoglobinopathies,19,20 which provides an impetus for widespread use on a global scale. To date, however, few studies have been completed in sub-Saharan Africa or other low-income set- tings where the burden of sickle cell disease is greatest.21 In addition to several small studies of hydroxyurea conducted in Nigeria,22-24 the Novel Use of Hydroxyurea in an African Region with Malaria (NOHARM) trial was a randomized, dou-

ble-blinded, placebo-controlled trial that was con- ducted at a single, large, urban site in Uganda, which showed that the rates of malaria were not higher with hydroxyurea than with placebo.25 However, the overall incidence of malaria in the NOHARM trial was very low, whereas the par- ticipants in the REACH trial lived in urban and rural areas of Africa that have a much higher in- cidence of malaria than Kampala, Uganda, where the NOHARM trial was conducted.

With full enrollment, high rates of adherence to trial visits and medication use, and a retention rate of nearly 95% in the trial over a period of 3 years, our trial showed that hydroxyurea treat- ment was both feasible and safe in sub-Saharan Africa. Despite frequent laboratory monitoring, dose-limiting toxic effects were uncommon in the first 3 months of treatment, and then the incidence did not increase further (Table 1). After 6 months of fixed-dose hydroxyurea therapy, dose escala- tion was not associated with unacceptable side effects or with toxic effects regarding laboratory variables and reached daily doses that were similar

Figure 2. Retention of Participants in the Trial.

The shaded area represents the 95% confidence interval for death or withdrawal from the trial. The inset shows the same data on an enlarged y axis.

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n engl j med 380;2 nejm.org January 10, 2019128

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n engl j med 380;2 nejm.org January 10, 2019 129

H y drox y ur e a for Sick le Cell A nemi a in A fr ic a

to those reported in the United States.26,27 Our re- sults indicate that a daily dose of approximately 20 mg per kilogram per day was reasonably effec- tive and not associated with dose-limiting toxic

effects. The trial was not designed to determine the appropriate amount or frequency of labora- tory monitoring.

The laboratory benefits of hydroxyurea treat-

Figure 3. Adverse Events before and during Hydroxyurea Treatment.

Error bars indicate 68% confidence intervals, which correspond to approximately 1 standard error.

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n engl j med 380;2 nejm.org January 10, 2019130

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

ment were evident, despite relative malnutrition in the REACH cohort, as compared with WHO child- growth standards and with populations of patients with sickle cell disease in the United States and Europe. Expected significant increases were ob- served in both the hemoglobin and fetal hemo- globin levels, along with significant decreases in the absolute neutrophil and reticulocyte counts, and these changes were sustained over time (Ta- ble 2). The mean increase in the hemoglobin level of 1 g per deciliter, despite suboptimal nutrition and ongoing risks of malaria and other infections, is important because the hemoglobin level is a well-established predictor of adverse outcomes in children with sickle cell anemia.28 Within 6 months after the start of treatment, expected clinical ben- efits were also observed with regard to sickle cell– related events such as pain and the acute chest syndrome, as well as all severe (grade ≥3) adverse events.

The benefits of hydroxyurea therapy with re- gard to malaria infections were significant — with a rate reduction of more than 50% — and were not predicted before the trial (Table 1), despite the lack of malaria chemoprophylaxis programs at all the clinical sites. This benefit was especially no- table after 12 months of treatment, so it may re- flect known inhibitory effects of fetal hemoglo- bin,29 more than direct effects by hydroxyurea,30 on parasite growth. The importance of this effect should be evident for sub-Saharan Africa, where Plasmodium falciparum malaria is a major killer of children and is especially lethal in those with sickle cell anemia.31 In a finding that perhaps reflects the decrease in the incidence of malaria, there was a significant reduction in the incidence of transfusions (Table 1), which is important be- cause of the general lack of safe blood supply across Africa.32

This trial showed a significant reduction in all-cause mortality in this young cohort (Table 1). This effect reflects the combined effect of fewer severe sickle cell–related clinical complications, infections, malaria, and possibly transfusions. However, because the REACH trial did not include a placebo control, the survival benefit could be due to hydroxyurea use but also to better overall care, since the participants had frequent visits while they were receiving treatment. However, these findings are similar to those of previous reports that have shown an effect of hydroxyurea therapy on survival.13,14,33,34

A limitation of this trial was the open-label treatment design without randomization or a placebo control, which was a decision that was based on strong opinions from the local ethics boards. However, the design fully addressed the key end points of feasibility and safety, showing that hydroxyurea could be administered in low- resource settings. All the participants received good care with close monitoring, which probably contributed to better outcomes that were unre- lated to hydroxyurea treatment; additional stud- ies will be needed to confirm sustained benefits with less monitoring. Strengths of this trial in- cluded the following: the international design; the dosing algorithm of a fixed dose followed by escalation to the maximum tolerated dose; the use of an electronic-capture system for data en- try; and the availability of an online dose calcu- lator to help ensure the safety of the participants. Long-term follow-up of this African cohort is ongoing for the investigation of growth and de- velopment and possible effects on organ function and fertility.

In conclusion, our results show that daily hydroxyurea treatment was feasible and safe for children with sickle cell anemia in sub-Saharan Africa. Moreover, hydroxyurea treatment reduced the rates of painful events, infection, malaria, transfusion, and death. Despite the recognition that 50 to 90% of affected children in Africa die before the age of 5 years,35 sickle cell anemia remains a neglected disease for which safe and effective treatment options are needed.36 As countries in sub-Saharan Africa begin newborn screening programs to identify children with sickle cell anemia,37-39 wider access to hydroxy- urea may provide a simple and inexpensive oral medication that can alter the disease course and prolong survival.

Supported by a grant (U01 HL133883, to Dr. Ware) and a Ca- reer Development Award (K23 HL128885, to Dr. McGann) from the National Heart, Lung, and Blood Institute, by the Cincinnati Children’s Research Foundation, and by Senior Research Fellow- ships (202800 and 091758, to Dr. Williams) from the Wellcome Trust.

No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the clinical teams and trial participants at the clin- ical trial sites in Luanda, Kinshasa, Kilifi, and Mbale; the direc- tor of the Kenya Medical Research Institute for permission to publish these results; and Drs. Margaret Ferris, Stephen Obaro, and Arnold Strauss for discussions at early stages of the trial.

n engl j med 380;2 nejm.org January 10, 2019 131

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